Phosphatidylinositol 3-kinase

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Phosphatidylinositol 3-kinase

Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate phosphatidylinositol and its phosphorylated derivatives at the 3′ position of the inositol ring, generating second messengers that control cellular activities and properties including proliferation, survival, motility and morphology — mutations in PI3K function disrupt these processes. PI3K proteins form a family that is divided into three classes that differ in structure, substrate preference, tissue distribution, mechanism of activation and, ultimately, in function. In regulating proliferation and in tumorigenesis, the most important PI3K proteins are those that belong to class IA — the catalytic subunit p110α and its associated regulatory subunit p85. In quiescent cells, p85 binds to p110α, stabilizing p110α and inactivating its kinase activity.

The high-affinity substrate of p110α is phosphatidylinositol 4,5-bisphosphate (PIP2). This is phosphorylated to become phosphatidylinositol 3,4,5-trisphosphate (PIP3 ), which then recruits proteins that contain a pleckstrin homology domain to cellular membranes. Among these are the serine-threonine kinase AKT, as well as its activating kinases PDK1. PIP3 is also a substrate of the phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10), which dephosphorylates PIP3 to generate PIP2 . PTEN is a negative regulator of PI3K signalling and functions as a tumour suppressor. Wild-type p110α is not oncogenic, but its growth-regulatory functions confer a potential for oncogenicity that can be activated by simple genetic changes.

It is now apparent that the activation of class 1a phosphoinositide 3-kinase (PI 3-kinase) is necessary and in some cases sufficient to elicit many of insulin's effects on glucose and lipid metabolism. The lipid products of PI 3-kinase act as both membrane anchors and allosteric regulators, serving to localize and activate downstream enzymes and their protein substrates. One of the major ways these lipid products of PI 3-kinase act in insulin signalling is by binding to pleckstrin homology (PH) domains of phosphoinositide-dependent protein kinase (PDK) and protein kinase B (PKB) and in the process regulating the phosphorylation of PKB by PDK.